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(Irinotecan, CPT-11)(Irinotecan, CPT-11)
Oncologic Drugs Advisory Committee ReviewOncologic Drugs Advisory Committee ReviewMarch 16, 2000March 16, 2000
CamptosarCamptosar
Pharmacia & UpjohnPharmacia & Upjohn
First-Line Therapy of Metastatic Colorectal CancerFirst-Line Therapy of Metastatic Colorectal Cancer
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Presentation AgendaPresentation Agenda
BackgroundBackground
2 Pivotal Phase III Controlled Clinical Trials2 Pivotal Phase III Controlled Clinical Trials– Improved Tumor ControlImproved Tumor Control
– Improved SurvivalImproved Survival
Summary and ConclusionsSummary and Conclusions
Q&AQ&A
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CPT-11 Presentation TeamCPT-11 Presentation Team
FunctionFunction NameName AffiliationAffiliation
MedicalMedical Langdon Miller, MDLangdon Miller, MD P&UP&UPaula Locker, MSPaula Locker, MS P&UP&UGabriela Gruia, MDGabriela Gruia, MD AventisAventis
BiostatisticalBiostatistical Nicoletta Pirotta, MSNicoletta Pirotta, MS P&UP&UGary Elfring, MSGary Elfring, MS P&UP&ULucile Awad, MSLucile Awad, MS AventisAventis
PharmacologyPharmacology Larry Schaaf, PhDLarry Schaaf, PhD P&UP&U
InvestigatorsInvestigators Leonard Saltz, MDLeonard Saltz, MD MSKCCMSKCCJean-YvesJean-Yves Douillard, MD Douillard, MD C GauducheauC GauducheauHanjochenHanjochen Wilke, MDWilke, MD K Essen-MitteK Essen-Mitte
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Development of metastases:Development of metastases:– 20% of patients have metastatic disease at presentation20% of patients have metastatic disease at presentation
– 40% of all patients will ultimately develop metastases40% of all patients will ultimately develop metastases
Deaths due to metastatic disease: 57,000 patientsDeaths due to metastatic disease: 57,000 patients
Standard first-line treatment: 5-fluorouracil (5-FU)Standard first-line treatment: 5-fluorouracil (5-FU)
Colorectal Cancer in 2000Colorectal Cancer in 2000
US Incidence: 130,000 patientsUS Incidence: 130,000 patients– 95,000 with colon cancer95,000 with colon cancer
– 35,000 with rectal cancer35,000 with rectal cancer
American Cancer Society. American Cancer Society. Cancer Facts & Figures 2000. Cancer Facts & Figures 2000.
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11 mo 11.5 mo
0
6
12
18
5-FUAlone
(N=578)
5-FULV
(N=803)
Survival (median)Survival (median)
5-FU Therapy: With and Without LV5-FU Therapy: With and Without LV
Adding LV to 5-FU significantly Adding LV to 5-FU significantly improves response rate but not survivalimproves response rate but not survival
Adding LV to 5-FU significantly Adding LV to 5-FU significantly improves response rate but not survivalimproves response rate but not survival
Meta-analysis Group in Cancer.Meta-analysis Group in Cancer. J Clin Oncol J Clin Oncol. 1992;10:896-903. 1992;10:896-903
Meta-analysis of 9 randomized trials (N=1,381)Meta-analysis of 9 randomized trials (N=1,381)
11%
23%
0%
10%
20%
30%
40%
5-FUAlone
(N=578)
5-FULV
(N=803)
Response RateResponse Rate
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5-FU Therapy: Infusional vs Bolus5-FU Therapy: Infusional vs Bolus
Infusional 5-FU significantly increases response Infusional 5-FU significantly increases response rate but median survival remains 12 monthsrate but median survival remains 12 months
Infusional 5-FU significantly increases response Infusional 5-FU significantly increases response rate but median survival remains 12 monthsrate but median survival remains 12 months
Meta-analysis Group in Cancer. Meta-analysis Group in Cancer. J Clin OncolJ Clin Oncol. 1998;16:301-308.. 1998;16:301-308.
Meta-analysis of 6 randomized trials (N=1,219)Meta-analysis of 6 randomized trials (N=1,219)
14%
22%
0%
10%
20%
30%
40%
5-FUBolus
(N=612)
5-FUInfusion(N=607)
Response RateResponse Rate
11.3 mo 12.1 mo
0
6
12
18
5-FUBolus
(N=612)
5-FUInfusion(N=607)
Survival (median)Survival (median)
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Novel agent with a new mechanism of action neededNovel agent with a new mechanism of action needed
CPT-11 Therapy of Colorectal CancerCPT-11 Therapy of Colorectal Cancer
CPT-11 offers:CPT-11 offers:– Topoisomerase I inhibitionTopoisomerase I inhibition
– Consistent activity in colorectal cancer Consistent activity in colorectal cancer
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First-Line, Single-Agent CPT-11 TherapyFirst-Line, Single-Agent CPT-11 Therapy
CPT-11 offers similar activity to that of 5-FU/LVCPT-11 offers similar activity to that of 5-FU/LVCPT-11 offers similar activity to that of 5-FU/LVCPT-11 offers similar activity to that of 5-FU/LV
*Conti. *Conti. J Clin OncolJ Clin Oncol. 1996;14:709-715. . 1996;14:709-715. ^Pitot. ^Pitot. J Clin OncolJ Clin Oncol. 1997;15:2910-2919.. 1997;15:2910-2919.
Results of US phase II trials (N=72)Results of US phase II trials (N=72)
32%
26%
0%
10%
20%
30%
40%
Trial 1*(N=41)
Trial 2^(N=31)
Response RateResponse Rate
12.1 mo 11.8 mo
0
6
12
18
Trial 1*(N=41)
Trial 2^(N=31)
Survival (median)Survival (median)
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RRAANNDDOOMMIIZZAATTIIOONN
CPT-11: 350 mg/mCPT-11: 350 mg/m22 every 3 weeks every 3 weeks
Best Supportive CareBest Supportive Care
PriorPrior5-FU5-FU
Second-Line CPT-11 Therapy Second-Line CPT-11 Therapy (V301)(V301)
Cunningham Cunningham et al. Lancetet al. Lancet. 1998; 352:1413-18... 1998; 352:1413-18..
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1111
00
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
00 33 66 99 1212 1515 1818 2121
MonthsMonths
Pro
bab
ilit
yP
rob
abil
ity
Second-Line SurvivalSecond-Line Survival(V301)(V301)
p=0.0001*p=0.0001*
* log-rank test* log-rank test
CPT-11CPT-11
BSCBSC
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RRAANNDDOOMMIIZZAATTIIOONN
CPT-11: 350 mg/mCPT-11: 350 mg/m22 every 3 weeks every 3 weeks
Infusional 5-FU-based regimenInfusional 5-FU-based regimen
PriorPrior5-FU5-FU
Second-Line CPT-11 Therapy Second-Line CPT-11 Therapy (V302)(V302)
Rougier Rougier et al. Lancetet al. Lancet. 1998; 352:1407-12.. 1998; 352:1407-12.
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1313
00
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.0 1.0
00 33 66 99 1212 1515 1818 2121
MonthsMonths
Pro
bab
ilit
yP
rob
abil
ity
Second-Line SurvivalSecond-Line Survival(V302)(V302)
p=0.04*p=0.04*
* log-rank test* log-rank test
CPT-11CPT-11
InfusionalInfusional5-FU5-FU
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Different mechanism of action from 5-FUDifferent mechanism of action from 5-FU
Rationale for First-LineRationale for First-LineCPT-11 Combination TherapyCPT-11 Combination Therapy
Hypothesis: First-line combination of CPT-11 with Hypothesis: First-line combination of CPT-11 with 5-FU/LV will further improve tumor control and survival5-FU/LV will further improve tumor control and survival
Hypothesis: First-line combination of CPT-11 with Hypothesis: First-line combination of CPT-11 with 5-FU/LV will further improve tumor control and survival5-FU/LV will further improve tumor control and survival
Active as first-line, single-agent therapy Active as first-line, single-agent therapy
Extends survival when used as second-line therapyExtends survival when used as second-line therapy
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*Saltz. *Saltz. J Clin OncolJ Clin Oncol. 1996;14:2959-2967. . 1996;14:2959-2967.
Weekly bolus regimenWeekly bolus regimen(Saltz -- Study 0007)(Saltz -- Study 0007)
Phase I Combination Dose-Finding Phase I Combination Dose-Finding and Pharmacokinetic Studiesand Pharmacokinetic Studies
Every-2-week infusional regimen Every-2-week infusional regimen (de Gramont -- Study F106)(de Gramont -- Study F106)
††Ducreux. Ducreux. J Clin OncolJ Clin Oncol. 1999;17:2901-2908.. 1999;17:2901-2908.
Weekly infusional regimenWeekly infusional regimen(AIO -- Study G101)(AIO -- Study G101)
‡‡Vanhoefer. Vanhoefer. J Clin OncolJ Clin Oncol. 1999;17:907-913. . 1999;17:907-913.
Addition of CPT-11 to existing schedules of 5-FU/LVAddition of CPT-11 to existing schedules of 5-FU/LV
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Pivotal Phase III TrialsPivotal Phase III Trials
Study Design and Conduct
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Pivotal First-Line TrialsPivotal First-Line Trials
Two independent, phase III, prospective, randomized, controlled, international studies
CPT-11/Infusional 5-FU/LVCPT-11/Infusional 5-FU/LVvsvs
Infusional 5-FU/LVInfusional 5-FU/LV
AventisAventisStudy V303Study V303
CPT-11/Bolus 5-FU/LVCPT-11/Bolus 5-FU/LV vs vs
Bolus 5-FU/LVBolus 5-FU/LV vsvs
((CPT-11 alone)CPT-11 alone)
Pharmacia & UpjohnPharmacia & UpjohnStudy 0038Study 0038
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Entry CriteriaEntry Criteria(0038)(0038)
Histologically proven colorectal cancerHistologically proven colorectal cancer
Unresectable measurable metastasesUnresectable measurable metastases
Performance status 0, 1 or 2Performance status 0, 1 or 2
No prior chemotherapy for metastatic diseaseNo prior chemotherapy for metastatic disease
>12 months since completion of adjuvant 5-FU>12 months since completion of adjuvant 5-FU
No prior pelvic radiotherapy permittedNo prior pelvic radiotherapy permitted
Adequate hematologic, renal, and hepatic functionAdequate hematologic, renal, and hepatic function
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Entry CriteriaEntry Criteria(V303)(V303)
Histologically proven colorectal cancerHistologically proven colorectal cancer
Unresectable measurable metastasesUnresectable measurable metastases
Performance status 0, 1 or 2Performance status 0, 1 or 2
No prior chemotherapy for metastatic diseaseNo prior chemotherapy for metastatic disease
>6>6 months since completion of adjuvant 5-FU months since completion of adjuvant 5-FU
Prior pelvic radiotherapy permittedPrior pelvic radiotherapy permitted
Adequate hematologic, renal, and hepatic functionAdequate hematologic, renal, and hepatic function
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TreatmentTreatment(0038)(0038)
Treatment continued until tumor progression or Treatment continued until tumor progression or unacceptable toxicityunacceptable toxicity
Supportive care for all study arms included:Supportive care for all study arms included:– Atropine for the treatment of cholinergic symptomsAtropine for the treatment of cholinergic symptoms
– Loperamide for the treatment of late diarrhea Loperamide for the treatment of late diarrhea
– Antiemetics for the prophylaxis of nausea and vomitingAntiemetics for the prophylaxis of nausea and vomiting
Second-line, post-study chemotherapy permittedSecond-line, post-study chemotherapy permitted
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TreatmentTreatment(V303)(V303)
Treatment continued until tumor progression or Treatment continued until tumor progression or unacceptable toxicityunacceptable toxicity
Supportive care for all study arms included:Supportive care for all study arms included:– Atropine for the treatment of cholinergic symptomsAtropine for the treatment of cholinergic symptoms
– Loperamide for the treatment of late diarrhea Loperamide for the treatment of late diarrhea
– Antiemetics for the prophylaxis of nausea and vomitingAntiemetics for the prophylaxis of nausea and vomiting
– Fluoroquinolone antibiotic for diarrhea in association with Fluoroquinolone antibiotic for diarrhea in association with grade 4 neutropenia or neutropenic fever
Second-line, post-study chemotherapy permittedSecond-line, post-study chemotherapy permitted
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EndpointsEndpoints(0038)(0038)
Time to tumor progression Time to tumor progression (primary)(primary)
Tumor response rateTumor response rate
SurvivalSurvival
SafetySafety
Quality of life (EORTC QLQ-C30)Quality of life (EORTC QLQ-C30)
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EndpointsEndpoints(V303)(V303)
Time to tumor progressionTime to tumor progression
Tumor response rate Tumor response rate (primary)(primary)
SurvivalSurvival
SafetySafety
Quality of life (EORTC QLQ-C30)Quality of life (EORTC QLQ-C30)
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Patient EvaluationPatient Evaluation(0038)(0038)
On-study assessmentsOn-study assessments– Tumor measurements Tumor measurements (q 6 weeks x 4, then q 12 weeks)(q 6 weeks x 4, then q 12 weeks)
– Performance status, weight, Performance status, weight, quality of life, chemistries quality of life, chemistries (Day 1 of each cycle)(Day 1 of each cycle)
– Adverse events, CBCs Adverse events, CBCs (weekly)(weekly)
Follow-up Follow-up – Post-study chemotherapyPost-study chemotherapy
– SurvivalSurvival
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Patient EvaluationPatient Evaluation(V303)(V303)
On-study assessmentsOn-study assessments– Tumor measurements Tumor measurements (q 6-7 weeks)(q 6-7 weeks)
– Performance status, weight, Performance status, weight, quality of life, chemistries quality of life, chemistries (Day 1 of each cycle)(Day 1 of each cycle)
– Adverse events, CBCs Adverse events, CBCs (weekly)(weekly)
Follow-up Follow-up – Post-study chemotherapyPost-study chemotherapy
– SurvivalSurvival
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Sample Size CalculationSample Size Calculation(0038)(0038)
Primary endpoint assumptionsPrimary endpoint assumptions– 40% improvement in TTP40% improvement in TTP
Statistical testStatistical test = 0.05 and 1-= 0.05 and 1- = 0.85 = 0.85 – Unstratified log-rank Unstratified log-rank
Sample sizeSample size– 220 patients per treatment arm220 patients per treatment arm
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Sample Size CalculationSample Size Calculation(V303)(V303)
Primary endpoint assumptionsPrimary endpoint assumptions– 40% improvement in response rate40% improvement in response rate
Statistical testsStatistical tests = 0.05 and 1-= 0.05 and 1- = 0.80 = 0.80 – Unstratified chi-squareUnstratified chi-square
Sample sizeSample size– 169 patients per treatment arm169 patients per treatment arm
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RRAANNDDOOMMIIZZAATTIIOONN
Stratification:Stratification:
PS (0 vs 1, 2)PS (0 vs 1, 2)
Age Age (< 65 yr vs (< 65 yr vs >> 65 yr) 65 yr)
Time from initial Time from initial diagnosisdiagnosis(< 6 mo vs (< 6 mo vs >> 6 mo) 6 mo)
Prior adjuvant Prior adjuvant therapy therapy (yes vs no)(yes vs no) CPT-11:CPT-11: 125 mg/m125 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks
CPT-11:CPT-11: 125 mg/m125 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks5FU:5FU: 500 mg/m500 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks
LV:LV: 20 mg/m 20 mg/m22/wk x 4 wks, q 6 wks/wk x 4 wks, q 6 wks
5FU:5FU: 425 mg/m425 mg/m22/d x 5 d, q 4 wks /d x 5 d, q 4 wks LV:LV: 20 mg/m 20 mg/m22/d x 5 d, q 4 wks/d x 5 d, q 4 wks
5-FU dose intensity=5-FU dose intensity=531531 mg/m mg/m22/wk/wk
5-FU dose intensity=5-FU dose intensity=333333 mg/m mg/m22/wk/wk
Treatment ArmsTreatment Arms(0038)(0038)
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CPT-11:CPT-11: 80 mg/m 80 mg/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wks5-FU:5-FU: 2.3 gm/m 2.3 gm/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wks AIOAIO
LV:LV: 500 mg/m500 mg/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wksoror
CPT-11:CPT-11: 180 mg/m 180 mg/m22 d1 q 2 wks d1 q 2 wks5-FU:5-FU: 400 IV/600 CI mg/m400 IV/600 CI mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks de Gramontde Gramont
LV:LV: 200 mg/m200 mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks
5-FU:5-FU: 2.6 gm/m 2.6 gm/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wks AIOAIOLV:LV: 500 mg/m500 mg/m22/wk x 6 wks, q 7 wks/wk x 6 wks, q 7 wks
oror5-FU:5-FU: 400 IV/600 CI mg/m400 IV/600 CI mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks de Gramontde Gramont
LV:LV: 200 mg/m200 mg/m22 d1, 2 q 2 wks d1, 2 q 2 wks
RRAANNDDOOMMIIZZAATTIIOONN
Treatment ArmsTreatment Arms(V303)(V303)
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Study Enrollment and Follow-UpStudy Enrollment and Follow-Up(0038)(0038)
Principal Investigator:Principal Investigator: Dr. Leonard SaltzDr. Leonard Saltz
Number of sites:Number of sites: 71 71 (Primarily North America)(Primarily North America)
Accrual period: Accrual period: May 1996 - May 1998May 1996 - May 1998
Survival cut-off: Survival cut-off: December 1999December 1999(19-month follow-up)(19-month follow-up)
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Study Enrollment and Follow-UpStudy Enrollment and Follow-Up(V303)(V303)
Principal Investigator:Principal Investigator: Dr. Dr. Jean-YvesJean-Yves Douillard Douillard
Number of sites:Number of sites: 83 83 (Primarily Europe)(Primarily Europe)
Accrual period: Accrual period: May 1997 - February 1998May 1997 - February 1998
Survival cut-off: Survival cut-off: October 1999October 1999(20-month follow-up)(20-month follow-up)
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Pivotal Phase III Trial ResultsPivotal Phase III Trial Results
Patient Characteristicsand Treatment Administration
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CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11
Intent-to-treat population Intent-to-treat population 231231 226226 226226
Never treated Never treated 4 4 8 8 4 4
Treated on another arm Treated on another arm 2 2 1 1 1 1
As-treated population As-treated population 225225 219219 223223
Patient EnrollmentPatient Enrollment(0038)(0038)
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV5-FU/LV
[AIO][AIO] [de Gramont][de Gramont] [AIO][AIO] [de Gramont][de Gramont]
RandomizedRandomized 199199 188188
Never treatedNever treated 11 11
Full-analysis populationFull-analysis population 198198 187187[53][53] [145] [145] [44][44] [143][143]
Treated on other armTreated on other arm 00 11
As-treated population As-treated population 199199 186 186 [54][54] [145] [145] [43][43] [143][143]
Patient EnrollmentPatient Enrollment(V303)(V303)
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CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=231N=231 N=226N=226 N=226N=226
Median age (yrs)Median age (yrs) 6262 6161 6161[range][range] [25-85][25-85] [19-85][19-85] [30-87][30-87]
Gender (% of pts)Gender (% of pts)
MM 6666 5555 6464 FF 3434 4545 3434
..
Performance status (% of pts)Performance status (% of pts) 00 3939 4242 4646
11 6161 5858 5454
DemographicsDemographics(0038)(0038)
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CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=198N=198 N=187N=187
Median age (yrs)Median age (yrs) 6262 6161[range][range] [27-75][27-75] [25-75][25-75]
Gender (% of pts)Gender (% of pts)
MM 6767 5353 FF 3333 4747
..
Performance status (% of pts)Performance status (% of pts) 00 5252 5151
11 4848 4949
DemographicsDemographics(V303)(V303)
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=231N=231 N=226N=226 N=226N=226
Primary site (% of pts)Primary site (% of pts)ColonColon 8181 8585 8484RectumRectum 1717 1414 1515
Number of involvedNumber of involvedorgan sites (% of pts)organ sites (% of pts)
1 1 6464 6666 6262>>22 3636 3434 3838
Liver involvement (% of pts)Liver involvement (% of pts) 8282 8282 8383
Disease CharacteristicsDisease Characteristics(0038)(0038)
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=198N=198 N=187N=187
Primary site (% of pts)Primary site (% of pts)ColonColon 5555 6565RectumRectum 4545 3636
Number of involvedNumber of involvedorgan sites (% of pts)organ sites (% of pts)
1 1 6262 6363>>22 3838 3737
Liver involvement (% of pts)Liver involvement (% of pts) 7777 8080
Disease CharacteristicsDisease Characteristics(V303)(V303)
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=231N=231 N=226N=226 N=226N=226
Median time from Median time from initial diagnosis (mo) initial diagnosis (mo) 1.9 1.9 1.71.7 1.8 1.8
[range][range] [0.1-161][0.1-161] [0.1-203][0.1-203] [0.1-186][0.1-186]
Prior adjuvant 5-FU Prior adjuvant 5-FU 1111 88 1010(% of pts)(% of pts)
Pelvic radiotherapy Pelvic radiotherapy 22 11 11(% of pts)(% of pts)
Disease HistoryDisease History(0038)(0038)
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=198N=198 N=187N=187
Median time from Median time from initial diagnosis (mo) initial diagnosis (mo) 4.5 4.5 2.72.7
[range][range] [0.1-88][0.1-88] [0.1-104][0.1-104]
Prior adjuvant 5-FUPrior adjuvant 5-FU 2626 2424(% of pts)(% of pts)
RadiotherapyRadiotherapy 2020 1616(% of pts)(% of pts)
Disease HistoryDisease History(V303)(V303)
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=231N=231 N=226N=226 N=226N=226
Abnormal baseline value (% of pts)Abnormal baseline value (% of pts)
Hgb <11 g/dLHgb <11 g/dL 2626 2525 2626
WBC WBC 8x108x1099/L/L 5252 5353 5151
LDH >ULNLDH >ULN 6060 5656 5353
Bilirubin >ULNBilirubin >ULN 7 7 4 4 1010
CEA CEA 100 ng/mL100 ng/mL 4040 3939 3737
Baseline Laboratory AbnormalitiesBaseline Laboratory Abnormalities(0038)(0038)
*ULN = upper limit of normal*ULN = upper limit of normal
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=198N=198 N=187N=187
Abnormal baseline value (% of pts)Abnormal baseline value (% of pts)
Hgb <11 g/dLHgb <11 g/dL 1616 2121
WBC WBC 8x108x1099/L/L 4747 3838
LDH >ULNLDH >ULN 4040 4444
Bilirubin >ULNBilirubin >ULN 7 7 7 7
CEA CEA 100 ng/mL100 ng/mL 3535 3232
Baseline Laboratory AbnormalitiesBaseline Laboratory Abnormalities(V303)(V303)
*ULN = upper limit of normal*ULN = upper limit of normal
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=225N=225 N=219N=219 N=223N=223
Median duration (mo)Median duration (mo) 5.55.5 4.14.1 3.93.9[range][range] [0.3-33][0.3-33] [0.4-22][0.4-22] [0.2-18][0.2-18]
..Median dose intensity (mg/mMedian dose intensity (mg/m22/wk) /wk) [Median relative dose intensity*][Median relative dose intensity*]
5-FU5-FU 236 236 [0.71][0.71] 457457 [0.86] [0.86] -- --
CPT-11CPT-11 60 60 [0.72][0.72] ---- 6262 [0.75] [0.75]
Treatment AdministrationTreatment Administration(0038)(0038)
*Ratio of actual dose intensity relative to planned dose intensity*Ratio of actual dose intensity relative to planned dose intensity
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CPT-11/5-FU/LV CPT-11/5-FU/LV 5FU/LV 5FU/LV N=199N=199 N=186 N=186
AIOAIO de Gramontde Gramont AIOAIO de Gramontde Gramont
N=54N=54 N=145N=145 N=43N=43 N=143N=143
Median duration (mo) Median duration (mo) 5.55.5 5.75.7 4.84.8 4.24.2 [range][range] [0.5-14.8][0.5-14.8] [0.5-15.7] [0.5-15.7] [0.2-10.6] [0.2-10.6] [0.5-11.5][0.5-11.5]
Median relative dose intensity *Median relative dose intensity *
CPT-11CPT-11 0.820.82 0.930.93 ---- ----
5-FU 5-FU 0.810.81 0.920.92 0.900.90 0.960.96
Treatment AdministrationTreatment Administration(V303)(V303)
*Ratio of actual dose intensity relative to planned dose intensity*Ratio of actual dose intensity relative to planned dose intensity
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Pivotal Phase III Trial ResultsPivotal Phase III Trial Results
Efficacy and Safety
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CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV5-FU/LV CPT-11CPT-11N=(231,198)N=(231,198) N=(226,187)N=(226,187) N=226N=226
Study 0038Study 0038 39%39% 21%21% 18%18%
Study V303Study V303 35% 35% 22%22%
Confirmed Response RatesConfirmed Response Rates (0038,V303) (0038,V303)
Responses confirmed Responses confirmed 4 weeks after initial objective response4 weeks after initial objective response*Chi-square test*Chi-square test
p<0.005*p<0.005*
p<0.0001*p<0.0001*
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CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV5-FU/LV CPT-11CPT-11N=(231,198)N=(231,198) N=(226,187)N=(226,187) N=226N=226
Median (0038) Median (0038) 7.0 mo7.0 mo 4.3 mo4.3 mo 4.2 mo4.2 mo
Median (V303) Median (V303) 6.7 mo 6.7 mo 4.4 mo4.4 mo
*Log-rank test*Log-rank test
Time to Tumor ProgressionTime to Tumor Progression (0038,V303) (0038,V303)
p=0.004*p=0.004*
p<0.001*p<0.001*
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4848
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24
Months
Pro
bab
ilit
y
CPT-11/5-FU/LV (N=231)
5-FU/LV (N=226)
* log-rank test* log-rank test
p=0.004*
Time to Tumor ProgressionTime to Tumor Progression(0038)(0038)
Page 49
4949
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15
Months
Pro
bab
ility
CPT-11/5-FU/LV (N=198)
5-FU/LV (N=187)
Time to Tumor Progression Time to Tumor Progression (V303)(V303)
p<0.001*
* log-rank test* log-rank test
Page 50
5050
Hazard RatioHazard Ratio FactorFactor Value Value [95% CI][95% CI] p-valuep-value
LDHLDH UNL vs >UNL UNL vs >UNL 0.600.60 0.00010.0001[0.47-0.76][0.47-0.76]
Organ sitesOrgan sites 1 vs 1 vs 2 sites2 sites 0.63 0.63 0.0001 0.0001 [0.50–0.80][0.50–0.80]
PSPS 0 vs 0 vs 1 1 0.74 0.74 0.0088 0.0088 [0.59–0.93][0.59–0.93]
BilirubinBilirubin UNL vs >UNL UNL vs >UNL 0.56 0.56 0.01320.0132[0.35–0.89][0.35–0.89]
HemoglobinHemoglobin < 11 vs < 11 vs 11 g/dL 11 g/dL 0.740.74 0.01570.0157[0.58–0.95][0.58–0.95]
AgeAge 65 vs <65 years65 vs <65 years 0.78 0.78 0.03150.0315[0.63–0.98][0.63–0.98]
TreatmentTreatment CPT-11/5-FU/LVCPT-11/5-FU/LV 0.640.64 0.00010.0001 vs 5-FU/LVvs 5-FU/LV [0.51–0.79][0.51–0.79]
*ULN=upper limit of normal*ULN=upper limit of normal
Cox Regression Analysis: TTPCox Regression Analysis: TTP(0038)(0038)
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5151
Hazard RatioHazard Ratio FactorFactor Value Value [95% CI][95% CI] p-valuep-value
Organ sitesOrgan sites 1 vs 1 vs 2 sites2 sites 0.73 0.73 0.0001 0.0001 [0.57–0.94][0.57–0.94]
LDHLDH UNL vs >UNL UNL vs >UNL 0.640.64 0.00120.0012[0.48-0.84][0.48-0.84]
TreatmentTreatment CPT-11/5-FU/LVCPT-11/5-FU/LV 0.590.59 0.00010.0001 vs 5-FU/LVvs 5-FU/LV [0.46–0.76][0.46–0.76]
Cox Regression Analysis: TTPCox Regression Analysis: TTP(V303)(V303)
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5252
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV5-FU/LV CPT-11CPT-11N=(231,198)N=(231,198) N=(226,187)N=(226,187) N=226N=226
Median (0038)Median (0038) 14.8 mo14.8 mo 12.6 mo12.6 mo 12.0 mo12.0 mo
Median (V303)Median (V303) 17.4 mo 17.4 mo 14.1 mo14.1 mo
Survival Survival (0038,V303)(0038,V303)
*Log-rank test*Log-rank test
p=0.042*p=0.042*
p=0.032*p=0.032*
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5353
0.0
0.10.2
0.3
0.40.5
0.6
0.7
0.80.9
1.0
0 6 12 18 24 30 36 42
Months
CPT-11/5-FU/LV (N=231)
5-FU/LV (N=226)
SurvivalSurvival(0038)(0038)
p=0.042*
Pro
bab
ilit
y
* log-rank test* log-rank test
Page 54
5454
Survival Survival (V303)(V303)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 6 12 18 24 30
Months
Pro
bab
ilit
y
CPT-11/5-FU/LV (N=198)
5-FU/LV (N=187)
p=0.032*
* log-rank test* log-rank test
Page 55
5555
Hazard RatioHazard Ratio FactorFactor Value Value [95% CI][95% CI] p-valuep-value
LDHLDH UNL vs >UNL UNL vs >UNL 0.470.47 0.00010.0001[0.37-0.60][0.37-0.60]
PSPS 0 vs 0 vs 1 1 0.57 0.57 0.0001 0.0001 [0.45–0.71][0.45–0.71]
WBCWBC <8 vs <8 vs 8 x 108 x 1099/L /L 0.640.64 0.00010.0001[0.51–0.80][0.51–0.80]
Organ sitesOrgan sites 1 vs 1 vs 2 sites2 sites 0.67 0.67 0.0004 0.0004 [0.54–0.84][0.54–0.84]
BilirubinBilirubin UNL vs >UNL UNL vs >UNL 0.55 0.55 0.00510.0051[0.35–0.86][0.35–0.86]
TreatmentTreatment CPT-11/5-FU/LVCPT-11/5-FU/LV 0.800.80 0.03720.0372 vs 5-FU/LVvs 5-FU/LV [0.64–0.99][0.64–0.99]
Cox Regression Analysis: SurvivalCox Regression Analysis: Survival(0038)(0038)
Page 56
5656
Hazard RatioHazard RatioFactorFactor ValueValue [95% CI][95% CI] p-valuep-value
LDHLDH UNL vs >UNL UNL vs >UNL 0.550.55 0.00010.0001[0.42-0.72][0.42-0.72]
PSPS 0 vs 0 vs 1 1 0.52 0.52 0.0001 0.0001 [0.41–0.67][0.41–0.67]
Time fromTime from 1 vs < 1 mo 1 vs < 1 mo .63.63 0.00050.0005Metastatic DxMetastatic Dx [0.49-0.82][0.49-0.82]
Organ sitesOrgan sites 1 vs 1 vs 2 sites2 sites 0.73 0.73 0.0127 0.0127 [0.57–0.94][0.57–0.94]
TreatmentTreatment CPT-11/5-FU/LVCPT-11/5-FU/LV 0.770.77 0.03650.0365 [vs 5-FU/LV][vs 5-FU/LV] [0.61–0.98][0.61–0.98]
Cox Regression Analysis: SurvivalCox Regression Analysis: Survival(V303)(V303)
Page 57
5757
CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11N=205N=205 N=203N=203 N=195N=195
Patients with any Patients with any 52%52% 70%70% 79%79%post-study therapypost-study therapy
CPT-11-basedCPT-11-based 1% 1% 38%38% 3% 3%CPT-11+5-FU-basedCPT-11+5-FU-based 13%13% 18%18% 9% 9%5-FU-based5-FU-based 30%30% 10%10% 64% 64%Other therapyOther therapy 8% 8% 4% 4% 3% 3%
Patients not treatedPatients not treated 48%48% 30%30% 21%21%
Post-Study TherapyPost-Study Therapy(0038)(0038)
56%56%
Page 58
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CPT-11/5-FU/LVCPT-11/5-FU/LV 5-FU/LV 5-FU/LV N=167N=167 N=171N=171
Patients with any Patients with any 49%49% 65%65%post-study therapypost-study therapy
CPT-11-basedCPT-11-based 2% 2% 28%28%CPT-11+5-FU-basedCPT-11+5-FU-based 4% 4% 6% 6% 5-FU-based5-FU-based 32%32% 21%21%Other therapyOther therapy 11%11% 10%10%
Patients not treatedPatients not treated 51%51% 35%35%
Post-Study TherapyPost-Study Therapy(V303)(V303)
34%34%
Page 59
5959
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV CPT-11 CPT-11Event (% of pts) Event (% of pts) N=225N=225 N=219N=219 N=223N=223
Diarrhea, grade 3/4Diarrhea, grade 3/4 2323 1313 3131
Grade 3Grade 3 1515 6 6 1818
Grade 4Grade 4 8 8 7 7 1313
Vomiting, grade 3/4Vomiting, grade 3/4 1010 4 4 1212
Mucositis, grade 3/4Mucositis, grade 3/4 2 2 1717 2 2
Neutropenia, grade 4Neutropenia, grade 4 2424 4343 1212
Neutropenic feverNeutropenic fever 7 7 1515 6 6
Neutropenic infectionNeutropenic infection 2 2 0 0 2 2
DiscontinuationsDiscontinuations 8 8 6 6 1212
Drug-related deathsDrug-related deaths 0.9 0.9 1.41.4 0.90.9
Adverse EventsAdverse Events(0038)(0038)
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6060
CPT-11/5-FU/LV CPT-11/5-FU/LV 5-FU/LV 5-FU/LV Event (% of pts) Event (% of pts) N=199N=199 N=186N=186
Diarrhea, grade 3/4Diarrhea, grade 3/4 2323 1111
Grade 3Grade 3 1717 7 7
Grade 4Grade 4 6 6 4 4
Vomiting, grade 3/4Vomiting, grade 3/4 6 6 3 3
Mucositis, grade 3/4Mucositis, grade 3/4 3 3 3 3
Neutropenia, grade 4Neutropenia, grade 4 9 9 1 1
Neutropenic feverNeutropenic fever 5 5 1 1
Neutropenic infectionNeutropenic infection 2 2 0 0
DiscontinuationsDiscontinuations 9 9 3 3
Drug-related deathsDrug-related deaths 0.5 0.5 0 0
Adverse EventsAdverse Events(V303)(V303)
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Quality of Life
Pivotal Phase III Trial ResultsPivotal Phase III Trial Results
Study 0038 primary endpointsStudy 0038 primary endpoints– Global health statusGlobal health status
– Role functioningRole functioning
– PainPain
Study V303 primary endpointStudy V303 primary endpoint– Global health statusGlobal health status
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6262
Global Health Status Subscale
-20
-15
-10
-5
0
5
10
15
20
0 4 8 12 16 20 24 28 32
Weeks
BetterBetter
WorseWorse
Me
an
Ch
an
ge
(s
e)
EORTC QLQ-C30 Quality of LifeEORTC QLQ-C30 Quality of Life(0038)(0038)
CPT-11/5-FU/LV
5-FU/LV
Page 63
6363
-20
-15
-10
-5
0
5
10
15
20
0 4 8 12 16 20 24 28 32
EORTC QLQ-C30 Quality of LifeEORTC QLQ-C30 Quality of Life(0038)(0038)
Weeks
BetterBetter
WorseWorse
Me
an
Ch
an
ge
(s
e)
Role Functioning Subscale
CPT-11/5-FU/LV
5-FU/LV
Page 64
6464
-20
-15
-10
-5
0
5
10
15
20
0 4 8 12 16 20 24 28 32
Weeks
WorseWorse
BetterBetter
Me
an
Ch
an
ge
(s
e)
Pain Subscale
EORTC QLQ-C30 Quality of LifeEORTC QLQ-C30 Quality of Life(0038)(0038)
CPT-11/5-FU/LV
5-FU/LV
Page 65
6565
Global Health Status Subscale
-20
-15
-10
-5
0
5
10
15
20
0 4 8 12 16 20 24 28 32
Weeks
BetterBetter
WorseWorse
Me
an
Ch
an
ge
(s
e)
EORTC QLQ-C30 Quality of LifeEORTC QLQ-C30 Quality of Life(V303)(V303)
CPT-11/5-FU/LV
5-FU/LV
Page 66
6666
Summary and ConclusionsSummary and Conclusions
Two independent, phase III, prospective, randomized,
controlled, multinational studies
Page 67
6767
Significantly lengthens time to tumor progressionSignificantly lengthens time to tumor progression
Efficacy SummaryEfficacy Summary
Significantly improves response rateSignificantly improves response rate
First-line combination CPT-11/5-FU/LV
Significantly prolongs survival Significantly prolongs survival
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6868
Safety SummarySafety Summary
Predictable and manageable side effect profilePredictable and manageable side effect profile
First-line combination CPT-11/5-FU/LV
Similar incidence of grade 4 diarrhea relative Similar incidence of grade 4 diarrhea relative to 5-FU/LVto 5-FU/LV
Low rates of grade 3/4 vomiting, mucositis, Low rates of grade 3/4 vomiting, mucositis, neutropenia, and febrile neutropenianeutropenia, and febrile neutropenia
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Quality of Life SummaryQuality of Life Summary
Prolongs life without compromising quality of lifeProlongs life without compromising quality of life
First-line combination CPT-11/5-FU/LV
Page 70
7070
ConclusionConclusion
CPT-11-based combination therapy sets CPT-11-based combination therapy sets a new standard in the first-line treatment of metastatic colorectal cancer
Page 71
7171
Proposed New IndicationProposed New Indication
CPT-11 should be indicated as a component of first-line therapy for patients with metastatic carcinoma of the colon or rectum
Recommended CPT-11/5-FU/LV regimens:
– Saltz
– de Gramont